Hyperuricemia: Allopurinol Decreases Cardiac Events?

By Dr. Geoffrey Modest

I have recently blogged on a Taiwanese study finding that in patients with gout, treating them with urate lowering therapy (ULT) was associated with a dramatically decreased incidence of cardiovascular disease (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/11/03/primary-care-corner-with-geoffrey-modest-md-uric-acid-lowering-cardiovasc-benefit-and-an-evolutionary-perspective/​ . The blog also has a section looking at an interesting evolutionary perspective on why great apes and humans developed a non-functioning uricase enzyme. A recent Danish epidemiologic study using allopurinol found the same decreased cardiovascular disease as the Taiwan study (see  doi.org/10.1016/j.amjmed.2015.11.003​).

Details:

• They looked at the medical data from all patients in Funen County in Denmark, scouring the blood samples done, all in- and out-patient hospital contacts, all reimbursed prescriptions and causes of death
• Of 65,971 people, 7127 had hyperuricemia (uric acid >= 6mg/dl), and propensity-score matched those on allopurinol with those not on a 1:1 basis, controlling for serum urate levels. (the propensity matching tries to maximize the balance between the study groups of covariates that are most likely to affect the outcome, e.g. excluding from the analysis people who had absolute indication or contraindication for taking the med, since they would disproportionately be in one group or the other)
• 73% male, median age 63, Charlson co-morbidity index was the same in both groups and 58% had a score of 0, 21% had ischemic heart disease, 20% hypertension, 11% atrial fibrillation, 5% alcoholism, 9% diabetes, mean serum urate 8.57 mg/dl in those on allopurinol and 8.24 in those not. Mean eGFR 64.
• Primary endpoint was composite of MI, stroke, or cardiovascular death; they also assessed all-cause mortality
• Results, comparing allopurinol users and nonusers:
  • ​There was an 11% decrease in MI, stroke and cardiovascular death​ [HR 0.89 (0.81-0.97)]. Over the 20-year followup, there was a pretty linear splaying of the curves, finding increasing benefit from allopurinol over time
  • There was a 32% decrease in all-cause mortality [HR 0.68 (0.62-0.74)]

So, a few points

• As noted in the prior blog, there are reasonably good studies finding that allopurinol:
  • Decreases hypertension in hyperuricemic adolescents
  • Decreases the rate of decline in renal function in patients with eGFR<60 over 24 months as well as a 71% decrease in cardiovascular events  (see Clin J Am Soc Nephrol 5: 1388), at an allopurinol dose of 100mg/d
  • Improves exercise capacity and time until chest pain in those with stable angina, even without hyperuricemia or gout (a small study of 65 patients with documented CAD, positive ETT chronic stable angina given allopurinol 300mg bid, a pretty high dose, with uric acid going from 6 mg/dl to 2 mg/dl — see lancet 2010; 9732: 2161)
  • Improves vascular oxidative stress and endothelial function
• A few prior observational studies have found a similar association between allopurinol and all-cause mortality, though this was not found in one study.
• A limitation of the current study is that they looked specifically at hyperuricemia, and the indication for allopurinol treatment was in those with gout. So, there may be some unaccounted for difference between those hyperuricemic patients who have had  gout vs those who was asymptomatic. There may also be an inherent bias in that those on allopurinol may have been less sick (though they did try to control for comorbidities), such that those near the end of life may not have been given the med, which might have disproportionately affected the rather extreme results noted on all-cause mortality.
• My bottom line is that there really is a pretty strong confluence of data which support the benefits of allopurinol/ULT in cardiovascular outcomes, including the physiologic data (endothelial function, oxidative stress), intermediate endpoint data (hypertension, exercise capacity in those with CAD, decrease in renal deterioration in those with CKD), an evolutionary rationale (as in prior blog), and a few observational studies finding benefits for clinical outcomes (the one from Taiwan and the current one). The Taiwanese study used 2 different ULT agents (allopurinol and benzbromarone​, now off the market), which makes it more likely that the clinical benefit is from lowering the uric acid level than a different non-urate lowering effect of allopurinol. But there is the strong caveat that there are still no randomized controlled trials which might clarify causality (these 2 trials are observational, so can only reveal an association, not causation). But over the past few years, I have been more aggressively prescribing ULT as my primary treatment of gout. Given the toxicity of the meds, I have not started screening for asymptomatic hyperuricemia and treating that. However, I suspect that would be beneficial, and perhaps we should be checking uric acid levels and at least recommending lifestyle modifications to decrease it when high (i.e., using hyperuricemia as another argument to reinforce the importance of decreasing obesity, alcohol, red meat, fructose, etc — see https://stg-blogs.bmj.com/bmjebmspotlight/2016/03/31/primary-care-corner-with-geoffrey-modest-md-gout-management-ahrq-report/ for AHRQ recommendations).